Aryltrifluoroethylamines

ABSTRACT

Certain arylmethyl amines have been prepared wherein the &#34;methyl&#34; carbon is substituted with a polyfluoroalkyl radical. The compounds form acid addition salts, exist in resolvable stereoisomeric forms, and are useful for treating hypertension. Formulations for human and veterinary medicine are described, as well as methods of use.

This application is a application of our previous patent applicationSer. No. 798,830 filed on May 20, 1977, now abandoned.

PRIOR ART

The prior art may be illustrated by the U.S. patent application Ser. No.585,024 to Malen and al.

SUMMARY

This invention relates to α-aryl (trifluoroethyl) amines of the formulaI ##STR1## in which A is oxygen, sulphur or an amino radical

B is CH═CH, oxygen, sulphur or an amino radical and

R₁, R₂, R₃ and R are either hydrogen or mineral or organic substituents.

The compounds of the formula I may be converted into an acid additionsalt, preferably a therapeutically-compatible acid addition salt.

The compounds of the formula I may be in a racemic form or resolved intotheir optical isomers.

This invention also relates to the process for preparing the compoundsfo formula I starting from a α-trifluoromethyl arylmethylamine of theformula II ##STR2## in which the meanings of the substituents remain thesame as previously given.

This invention further relates to pharmaceutical compositions intendedfor human and veterinary medicine which comprises a compound of formulaI or a salt thereof in admixture with an inert carrier or diluent.

The pharmaceutical compositions found an use for treating hypertensionin mammals.

PREFERRED EMBODIMENTS

This invention relates to novel substituted aryl lower alkylamines. Moreprecisely it relates to aryl methylamines, the methyl group of which issubstituted by one or more polyfluoromethyl radicals.

This invention specifically provides the aryl (trifluoroethyl) amines ofthe formula I ##STR3## wherein R₁ and R₂, the same or different, arehydrogen, a lower alkoxy radical, a lower alkylradical or a halogen.

R₃ is hydrogen, a methyl or an ethyl radical

R₄ is hydrogen, a methyl, an ethyl or a cyclopropyl radical

R is a hydrogen when R₁ and/or R₂ are different from hydrogen or is alower alkyl when R₁ and/or R₂ are hydrogen

A is a heteroatom selected from the group consisting of oxygen, sulphuror an imino radical

B is bridge atom selected from the group consisting of --CH═CH--,oxygen, sulphur and the grouping >N--R₅ wherein R₅ is hydrogen or alower alkyl radical

m is zero or 1

n is zero, 1 or 2

This invention also provides the salts of a compound of formula I with amineral or organic acid, preferably a therapeutically-compatible mineralor organic acid.

This invention further provides the optically-active isomers of acompound of formula I or an acid addition salt thereof and preferablythe levorotatory isomers.

Among the compounds of formula I it may be particularly cited:

(a) The oxazolines of formula I_(A), in a racemic or optically-activeform ##STR4## wherein the substituents R₁, R₂, R₃, R₄ R and n aredefined as above, and specifically

dl α-trifluoromethyl 2-[(furyl-2) methylamino]oxazoline

dl α-trifluoromethyl 2-(4-chlorobenzylamino)oxazoline

dl α-pentafluoroethyl 2-benzylamino oxazoline

dl α-trifluoromethyl 2-(4-methoxy benzylamino)oxazoline

dl α-trifluoromethyl 2-benzylamino oxazoline

-trifluoromethyl 2-benzylamino oxazoline(dextrorotatory isomer)

dl α-trifluoromethyl 2-(3-trifluoromethyl benzylamino)oxazoline

α-trifluoromethyl 2-benzylamino oxazoline (levorotatory isomer)

dl α-trifluoromethyl 2-[(thienyl-2)methylamino]oxazoline

dl α-trifluoromethyl 2-(N-methylpyrrolyl-2)methylamino oxazoline.

dl α-trifluoromethyl 2-(2-methylbenzylamino)oxazoline.

dl α-trifluoromethyl 2-[(pyrrolyl-2) methyl amino] oxazoline

dl α-trifluoromethyl 2-(N-methylbenzylamino) oxazoline.

(b) The thiazolines of formula I_(B) in a racemic or optically-activeform ##STR5## wherein the meanings of the substituents R, R₁, R₂, R₃,R₄, and n remain unaltered and specifically dl α-trifluoromethyl2-benzylamino thiazoline

(c) the tetrahydro m-oxazines of the formula I_(C) ##STR6## in which thedefinitions of the substituents R, R₁, R₂, R₃, R₄, and n remain the sameas above in a racemic or optically-active form and specifically dlα-trifluoromethyl 2-benzylamino 4,5,6-tetrahydro 1,3-oxazine.

(d) The imidazolines of the formula I_(D), in a racemic oroptically-active form ##STR7## wherein the substituents R, R₁, R₂, R₃,R₄, and n are defined as above-given and specifically dlα-trifluoromethyl 2-benzylamino imidazoline.

(c) The tetrahydropyrimidines of formula I_(E) in a racemic oroptically-active form, ##STR8## wherein the substituents R, R₁, R₂, R₃,R₄, and n are defined as above-given and specifically dlα-trifluoromethyl 2-benzylamino 4,5,6-tetrahydropyrimidine.

As far as this invention is concerned, the term lower alkyl denotes ahydrocarbon straight or branched chain having from 1 to 6 carbon atoms,optionally bearing a hydroxy, lower acyloxy, a lower alkoxy or adiethylamino substituent. Examples of lower alkyl radicals are methyl,butyl, isopentyl, n-hexyl or hydroxybutyl.

The term lower alkoxy denotes a lower alkyloxy radical wherein the termlower alkyl is similarly defined. Examples of such alkoxy radicals aremethoxy, ethoxy, iso propoxy, sec butyloxy, neo pentyloxy, tertbutyloxy,n-hexyloxy, β-ethoxy β-ethoxy, diethylaminoethoxy radicals.

The term "halogen" designates a fluorine or a chlorine atom. It may bealso a iodine or a bromine atom.

The compounds of formula I may be easily salified by adding a mineral ororganic acid. Examples of suitable acids are hydrochloric acid,hydrobromic acid, sulphuric acid, phosphoric acid, nitric acid, formicacid, acetic acid, di-propyl acetic acid, tartaric acid, citric acid,maleic acid, pamoic acid, itaconic acid, benzoic acid, thiazole5-carboxylic acid, nipecotic acid, glucose-1-phosphoric acid, methanesulphonic acid, isethionic acid and benzene sulphonic acid.

The compounds of formula I and the acid addition salts thereof areendowed with interesting pharmacological properties, namely hypotensiveproperties. They exert only very weak neutrological effects and maytherefrom be used as a drug, namely as an anti-hypertensive drug withouta fear of noxious side-effects, such as sedation or sleepiness.

This invention further extends to pharmaceutical compositions containingas active ingredient at least one compound of formula I or an acidaddition salt thereof in admixture or conjunction with an inertnon-toxic pharmaceutically-acceptable carrier or diluent.

The so-defined pharmaceutical compositions may be those intended fororal, parenteral, sublingual, percutaneous or rectal ways ofadministration. They are in the form of tablets, coated tablets,capsules, soft gelatine capsules, dragees, drinkable solutions orsuspensions, drops; injectible suspensions or solutions, solutions in apolar solvent for percutaneaous use, sublingual tablets, suppositoriesand the like.

The injectible solutions or suspensions may be packed in the form ofampuls, multidosage flasks, or self-injectible syringes.

The useful posology may vary broadly depending on the age and the weightof the patient, the way of administration and the severity of thetherapeutic indication. Usually in human medicine the posology may rangefrom 0.1 mg to 2 mg per unit dosage and from 0.1 to 5 mg per day in theman. In veterinary medicine the pharmaceutical compositions may also beused and the amount of active ingredient is then adapted to the speciesto be treated.

The pharmaceutical compositions are prepared according to known methods.Among the inert carriers or diluents they may be particularly citedtalc, the starches, magnesium stearate, calcium carbonate, magnesiumphosphate, silica, lactose for the tablets, distilled water or salinesolutions for the injectible solutions or suspensions, benzyl alcoholfor the percutaneous solutions; cocoa butter or polyethylene glycolstearates for the suppositories.

This invention still provides a process for preparing the aryl(trifluoroethyl) amines of formula I ##STR9## wherein the substituentsR, R₁, R₂, R₃, R₄, A, B, n and m have the previously-given definitionsand the acid-addition salts thereof in which an αaryl (trifluoroethyl)amine of formula II ##STR10## wherein the substituents B, R, R₁, R₂, R₃,R₄ and n have the previously-given meanings is condensed, either with a(ω-halogenoalkyl) isocyanate or isothiocyanate having the formula III.

    A═C═N--(CH.sub.2).sub.m' --CH.sub.2 Hal            (III)

in which

A is oxygen or sulphur

Hal is a chlorine, bromine or iodine and

m' is an integer of 1 to 3

to produce a ω-halogeno alkyl Urea or thio-Urea of formula IV ##STR11##in which the substituents R, R₁ R₂, R₃, R₄, A, B, Hal, n and m' have theabove-given definitions.

Which is cyclized by heating in an aqueous medium to form a compound offormula I' ##STR12## in which A is oxygen or sulphur and thesubstituents B, R, R₁, R₂, R₃, R₄, n and m have the above-givendefinitions, which may be further salified by adding a mineral ororganic acid or resolved into their optical isomers by means of anoptically-active organic acid.

Either with a S-methyl isothiourea of the formula V ##STR13## wherein mis defined as above-given, to produce a compound of formula I" ##STR14##in which the substituents R, R₁, R₂, R₃, R₄, B, n and m are defined aspreviously given and for which A is an imino radical.

Which may be further salified by adding a mineral or organic acid orresolved into their optical isomers. Compounds of this inventionaccording to formula I are also advantageously prepared by reacting anα-aryl(trifluoroethyl)amire of formula II with an(alkali-metal)thiocyanate in the presence of an acylating agent to produce anacylthioUrea of the formula VI ##STR15## in which the substituents B, R,R₁, R₂, R₃, R₄ and n are defined as previously-given and Z is a loweralkyl radical, a phenyl radical or a phenyl radical substituted with ahalogen or a lower alkoxy then saponifies the acyl radical in alkalinemedium to produce a thiourea of the formula VII ##STR16## in which thedefinitions of the substituents remain unaltered.

Which is further alkylated by means of an alkylating agent to form aS-lower alkyl thiourea of the formula VIII ##STR17## in which R₅ is alower alkyl radical and R, R₁, R₂, R₃, R₄, B and n have the above-givendefinitions, condenses the latter with an alkylene diamine of theformual IX.

    .sub.2 HN--(CH.sub.2).sub.p --NH.sub.2                     (IX)

in which p is an integer of 2 to 4 and recovers a compound of formula(I") ##STR18## wherein the definitions of the substituents remainunaltered.

Which may be further salified by adding a mineral or organic acid orresolved into their optical isomers.

The process according to the invention may also be defined by thefollowing features, which are presently preferred:

(a) the condensation of an amine of formula II with an ω-halogenoalkylisocyanate or isothiocyanate of formula III is performed in an inertorganic solvent such as a linear or cyclic ether at a temperature ofabout 0° to about 10° C.,

(b) the cyclisation of the ω-halogenoalkyl Urea or thiourea of formulaIV is performed by heating at a temperature ranging from 50° to 150°,preferably in an aqueous medium, in the presence or absence of ahydracid acceptor such as an alkalimetal carbonate or a triloweralkylamine,

(c) the condensation of the amine of formula II with a S-methylisothiourea of formula V is performed in a polar solvent such aspyridine, dimethylformamide, dimethyl acetamide,hexamethylphosphorotriamide and at a temperature ranging from 80° to120°,

(d) the S-methyl isothiourea of formula V is preferably used as an acidaddition salt, providing a compound of formula I" as a salt,

(e) the alkali-metal thiocyanate is preferably ammonium thiocyanate,

(f) the acylating agent is an acid chloride and more precisely a loweralkyl carboxylic acid chloride, benzoyl chloride, or a substitutedbenzoic acid chloride,

(g) the saponification of the acylthiourea of formula VI is carried outby means of an alkalimetal hydroxide such as potash or soda,

(h) the alkylating agent is a lower alkylhalide, a lower alkyl sulphateor a lower alkyl arylsulphonate such as methyl iodide or ethyl sulphate,

(i) the condensation of the alkyl isothiourea of formula VIII with thelower alkylene diamine of formula IX is carried out by heating thereactants in a high-boiling solvent such as pyridine, butanol, orisopropanol.

This invention further includes a process for preparing the α-aryltrifluoroethylamines of formula II which consists in reacting a halogenoarene of the formula X ##STR19## wherein the definitions of thesubstituents R, R₁, R₂ and B are those previously given and Hal is achlorine or a bromine with a metal selected from the group consisting ofmagnesium and cadmium, to produce the corresponding organometallicderivative, condensing the latter with a trifluoroacetic acid of theformula XI

    CF.sub.3 --(CF.sub.2).sub.n --COOH                         (XI)

wherein n has the above-given definitions recovering an aryltrifluoromethylketone of the formula XII ##STR20## wherein R, R₁, R₂, Band n have the above-given definitions which may either be condensedwith a hydroxylamine derivative of the formula XIII

    .sub.2 HN--OR.sub.6                                        (XIII)

in which R₆ is a hydrogen or a lower alkyl radical/to provide thecorresponding oxime of the formula XIV ##STR21## in which thedefinitions of the substituents remain unaltered and reducing the latterby means of sodium in a lower alkanol, an alkalimetal mixed hydride orof diborane to obtain the desired compound of formula II in which R₃ andR₄ are hydrogen, or be condensed with a metal alkyl to produce atertiary carbinol of the formula XV ##STR22## in which R, R₁, R₂, B andn have the above-given definitions, and R₄ is a methyl radical, an ethylradical or a cyclopropyl radical reacting this compound with a cyanogenhalide to form the corresponding carbamate, and hydrolysing the latterin acidic medium to produce a compound of formula XVI ##STR23## in whichR, R₁, R₂, R₄ B and n have the above-given definitions and for which R₃is a hydrogen.

In order to get an α-aryl(trifluoroethyl)amine of formula II in which R₃is a methyl or ethyl radical, an α-aryl(trifluoroethyl)amine of formulaII in which R₃ is hydrogen, is condensed with, formaldehyde oracetaldehyde then the resulting Schiff's Base is reduced into a N-methylor ethyl derivative by means of catalytic hydrogenation or an alkalimetal mixed hydride.

The N-methylation may also be performed by reacting the amino derivativewith a lower alkyl chloroformate and reducing the resulting alkylcarbamate by means of an alkali metal mixed hydride to produce aN-methyl derivative.

In the process for producing the compounds of formula II the alkyl metalderivative is preferably an alkyl magnesium halide, an alkyl cadmiumhalide, an alkyl zinc halide, an alkyl mercury halide, or an alkylcopper halide.

The cyanogen halide is preferably a bromide or a chloride.

The hydrolysis of the isocyanate into the carbamate is carried out witha strong acid, preferably a mineral acid as for example hydrochloricacid or sulphuric acid.

The resolution of the compounds of formula I may be performed bysalifying a compound of formula I in racemic form with anoptically-active acid such as a carboxylic acid for example d-tartaric,NN dimethyl d-tartramic acid, d-camphoric acid, abietic acid,d-Ketogulonic acid, ascorbic acid, 1-menthoxyacetic acid; a sulphonicacid as for example d-camphosulphonic acid; a phosphoric acid as forexample glucose 1-phosphoric acid, d-glucose 1,6-diphosphoric acid, anoptically-active bis-naphtyl phosphoric acid.

The resolution may also be performed at an earlier step and namely onthe ω-halogeno alkyl Ureas or thioureas of the formula IV or onaryl(trifluoroethyl)amines of the formula II. At these steps the sameresoluting agents may be utilized as for the compounds of the formula I.

This invention further exends to the intermediate compounds used orproduced during the performance of the processes:

(a) the oximes of formula XIV ##STR24## wherein the definitions of thesubstituents remain the same than those previously given

(b) the aryl(trifluoroethyl)amines of formula II ##STR25## in which thedefinitions of the substituents R, R₁ R₂, B, R₃, R₄ and n remainunaltered, in a racemic or optically-active form,

(c) the (ω-halogenoalkyl)Ureas or Thioureas of formula IV ##STR26##wherein the definitions of the substituents R, R₁ R₂, R₃, R₄, B, n, m'and Hal remain unaltered and A is oxygen or sulphur,

(d) the n-acyl Thioureas of the formula VI ##STR27## wherein thedefinitions of the substituents R, R₁, R₂, R₃, R₄, B and n remainunaltered and Z is a lower alkyl radical, a phenylradical or a phenylradical substituted with a halogen or a lower alkoxy radical,

(e) the thioureas of the formula VII ##STR28## wherein the substituentsR, R₁, R₂, R₃, R₄, B and n are defined as previously-given

(f) the alkyl isothio Ureas of the formula VIII ##STR29## wherein R, R₁R₂, R₃, R₄, B and n are defined as above-given and R₅ is a lower alkylradical.

It may also be of interest to produce the compounds of general formulaXII in which B is an oxygen atom, a sulphur atom or an imino group N-R₅by direct acylation of the corresponding aromatic derivative with ananhydride of the formula (CF₃ (CF₂)_(n) CO)₂ O in a chlorinated solventsuch as dichorethane or trichlorethane.

The following examples are merely intended to illustrate the invention.They do not limit it in any manner.

EXAMPLE I α-phenyl 2-(trifluoroethylamino) imidazoline Step A N(α-phenyl trifluoroethyl) N'benzoylthio Urea

8.2 g ammonium thiocyanate are dissolved in 54 ml water and theresulting solution is cooled to about 0°. The temperature is kept tothis temperature during the addition of a solution of 11.5 ml benzoylchloride in 10.5 ml acetone thereto. The temperature of the reactionmixture is let to revert to about 30° then the mixture is heated toreflux for 10 mn. A solution of α-phenyl trifluoroethylamine in 110 mlacetone is thereafter added portionwise for 1 hour while heating themixture at reflux. The heating is maintained for a further period of11/2 hour then let to revert to ambient temperature. The solvent isdistilled off. The dry residue is taken up in 250 ml water. The aqueoussolution is extracted 3 times with 200 ml ether. The organic phases areunited, washed with water until the washings are free of chlorine ions,filtered and dried on sodium sulphate. The solvent is evaporated off,under reduced pressure and 34.1 g of raw product are recovered. Thecompound is purified by recrystallizing it from hexane. The pureN-(α-phenyl trifluoroethyl) N'-benzoyl thio Urea melts at 55°-60°.

Step B

In flask there are successively poured 31 g N-(α-phenyltrifluoroethyl)N'-benzoylthio Urea 175 ml ethanol and 27 ml N solution of sodiumhydroxide. The whole mixture is kept under stirring for 36 hours at roomtemperature. Ethanol is thereafter evaporated under reduced pressure andit remains an oily residue which is twice extracted with 100 ml ether.The ethereous phases are united, whashed with water until neutral,dried, filtered then evaporated to dryness.

20.3 g of a raw product are thus recovered. Crystallisation is initiatedby triturating with few ml of heptane.

14.9 g N-(α-phenyltrifluoroethyl) thio Urea are thus obtained i.e. ayield of 72%. The pure compound is further recrystallised from a mixtureof cyclohexane-Benzene. It melts at 115°-125°.

Step C N-(α-phenyltrifluoroethyl) S-methyl isothio Urea

14.5 g N-(α-phenyltrifluoroethyl) thio Urea are dissolved in 270 mlacetone and this solution is heated to reflux. A solution of 17.6 gmethyl iodide in 7.75 ml acetone is added thereto while keeping theheating at reflux during the addition and for a further period of threehours. The solvent is thereafter evaporated off and 25 of an oilyproduct is obtained. The crystallisation thereof is initiated byscratching in the presence of benzene. The crystalls melt at 138°-144°.A further crystallisation supplies 18.5 g of pure N-(α-phenyltrifluoroethyl) S-methylisothiourea in the form of its hydroiodidemelting at 142°-144°.

The evaporation of the mother liquors provides a second crop weighing3.8 g.

STEP D

2-(α-phenyltrifluoroethylamino) imidazoline, 0.88 g of ethylene diaminein 1 ml ethanol are added to a solution of 6.6 g N. (α-phenyltrifluoroethyl) S-methyl isothiourea (hydroiodide) in a mixture ofethanol and isoamyl alcohol. The mixture is heated to reflux until theprecipitate disappears and the evolution of ammoniac and methylmercaptan ceases. The reflux lasts about 6 hours and the solution is letto revert to room temperature, then kept in a cool place for a night.The solvent is thereafter evapored off. The crystallisation is initiatedby scratching. The thus formed crystalls are taken up in few mlisopropyl ether. By evaporating the solvent, 6.9 g of2-(α-phenyltrifluoroethylamino) imidazoline (hydroiodide) are obtained.The product is purified by recrystallising from 15 ml ethyl acetate. Thesolution is filtered and evaporated off. A pure compound is obtainedweighing 3.4 g and melting at 180°-190°. A further recrystallisationfrom water provides 3.1 g of 2. (α-phenyltrifluoroethylamino)imidazoline (hydroiodide) i.e. a yield of 49%. Theanalytical sample melts at 188°-190°.

The hydroiodide is further converted into the free base by adding asolution of sodium hydroxyde to it- 1.8 g of 2(α-phenyltrifluoroethylamino) imidazoline are obtained after recrystallisationfrom acetonirile in the cold. The compound melts at 178°-182° (sublim).

2-(α-phenyl trifluoroethylamino) imidazoline is soluble in thestoichiometric amount of N/10 hydrochloric acid solution.

    ______________________________________                                        Analysis : C.sub.11 H.sub.12 F.sub. 3 N.sub.3 = 243.34                                    C       H         N %                                             ______________________________________                                        Calculated    54.31     4.98      17.27                                       Found         54.54     5.37      17.21                                       ______________________________________                                    

EXAMPLE II dl 2-(α-trifluoromethyl benzylamino) tetrahydropyrimidine

Using the same procedure as in example I step D starting from 6.6 g ofN-(α-phenyl trifluoroethyl) S-methyl isothiourea in 70 ml iso amylalcohol and 1.3 g diaminopropane in 23 ml isoamyl alcohol, 3.9 g of[2-(α-phenyl (trifluoroethylamino)] tetrhydropyrimidine are obtained(i.e. a yield of 58%), as its hydroiodide. It melts at 196°-202° afterrecrystallisation from ethyl acetate then from water.

This hydroiodide is then converted into the free base by adding normalsolution of sodium hydroxide. The free base is thereafter taken up inmethylene chloride and added with an ethanolic solution of hydrochloricacid until the pH value reaches 2. The solvent is thereafter evaporatedoff and the oily residue is taken up with ethyl acetate from which itcrystallises. The hydrochloride is further purified by recrystallisingit from isopropanol. The pure hydrochloride melts at 206°-210°.

    ______________________________________                                        Analysis : C.sub.12 H.sub.14 F.sub.3 N.sub.3, C1H = 293.725                             C      H        N        C1 %                                       ______________________________________                                        Calculated  49.07    5.16     14.29  12.07                                    Found       48.89    5.24     14.20  12.03                                    ______________________________________                                    

EXAMPLE III dl 2-[α-(trifluoromethyl) benzylamino] oxazoline Step A dlN-(α-phenyl trifluoromethyl) N'-(αchloroethyl) Urea

A solution of 7.4 g of dl (α-phenyl trifluoroethyl)amine in 40 ml etheris added with a cool solution of 4.3 g β-chloroethyl isocyanate in 25 mlether dropwise for 30 mn. During this addition the mixture is kept at 0°to -5° C. then kept under stirring for 24 hours at room temperature. Thethus formed precipitate is filtered, washed with ether and dried-7.9 gof N-(α-phenyltrifluoroethyl) N'-(β-chloroethyl) Urea are isolated (i.e.a yield of 67%). The thus obtained compound melts at 127°-132°. It isused as such for the next step.

Step B

7.6 g of N-(α-phenyl trifluoroethyl) N'-(β-Chloroethyl) Urea aresuspended in 60 ml water, then 4.3 ml triethylamine are added and thewhole mixture is heated to reflux under stirring for 30 mn. The reactionmixture is let to revert to about 20°, the precipitate is separatedwhich is dried, washed with water until the washings are neutral anddried under vacuum-6.3 g 2-[α-trifluoromethyl) benzylamino] oxazolineare obtained i.e. a yield of 95%. For analytical purpose the compound isrecrystallized from isopropanol with a yield of 73%. The analyticalsample melts at 162°-168° (sublim).

    ______________________________________                                        Analysis C.sub.11 H.sub.11 F.sub.3 N.sub.2 O = 244,22                                     C       H         N %                                             ______________________________________                                        Calculated    54.10     4.54      11.47                                       Found         53.98     4.55      11.34                                       ______________________________________                                    

The starting compound, α-phenyl trifluoroethylamine is obtainedaccording to the process described by R. A. Shepart J. org. Chem. 32(1967) 3197.

EXAMPLE IV dl [(α-trifluoromethyl) (3-trifluoromethyl benzylamino)]oxazoline Step A (3-trifluoromethyl phenyl) trifluoromethyl Ketoxine

7.8 g of hydroxylamine hydrochloride are dissolved in 250 ml of amixture of ethanol and pyridine and to this solution 7 g(m-trifluoromethyl phenyl) trifluoromethyl Ketone are added. The mixtureis heated to reflux for 16 hours, then cooled and diluted with 100 mlwater. The oxime precipitates and is separated by filtration, dried,washed with water many times, and dried again. The yield amounts to 42%.

(3-trifluoromethyl phenyl) trifluoromethyl Ketoxime melts at 63°-65°.

The starting material (m-trifluoromethylphenyl) trifluoromethyl Ketoneis obtained according to the process described by R-Fuks and G. J. PorkJ. org. Chem. 22 (1957) 993

Step B dlα-(3-trifluoromethyl phenyl) (trifluoroethyl) amine

2.5 g (3-trifluoromethyl phenyl) trifluoromethyl Ketoxime are suspendedin 40 ml isopropyl ether and to this suspension 4 g lithium aluminiumhydride are added. The mixture is heated to reflux for 3 hours thencooled. The excess of reagent is destroyed by cautious addition of anaqueous solution of tartaric acid. The mixture is made basic by addingsodium hydroxide and the ethereous phase is separated. The aqueous phaseis further extracted with isopropyl ether; the organic solutions areunited, washed with water, dried an evaporated off under reducedpressure.

The residue is purified by fractional distillation-dlα-(3-trifluoromethyl phenyl) (trifluoroethyl) amine is thus obtainedwith a yield of 72%. This compound is a liquid which boils at 82°-83°under 15 mm Hg.

n_(D) ²³ =1,4250.

Step C dl N-[α-(3-trifluoromethyl phenyl)trifluoroethyl]N'-(βchloroethyl) Urea

Using the same procedure as at step A of example III and starting fromdl α-(3-trifluoromethyl) phenyl) trifluoroethyl) amine and β-chloroethylisocyanate, N-[α-(3trifluoromethylphenyl) trifluoroethyl]N'-(β-chloroethyl) Urea is obtained with a theorectical yield. It meltsat 124°-128°.

Step D dl 2-[α-(trifluoromethyl) (3-trifluoromethyl benzylamino)]oxazoline

Using the same procedure as in example III step B and starting fromN-[α-(3-trifluoromethyl phenyl) trifluoroethyl] N'-(β-chloroethyl) Urea,dl 2-[α-(trifluoromethyl) 3-trifluoromethyl benzylamino)] oxazoline isproduced. It melts at 129°-132°.

    ______________________________________                                        Analysis C.sub.12 H.sub.10 F.sub.6 N.sub.2 O = 312,22                                     C       H         N %                                             ______________________________________                                        Calculated    46.16     3.23      8.96                                        Found         46.45     3.48      8.85                                        ______________________________________                                    

EXAMPLE V dl 2-(α-trifluoromethyl benzylamino) 4,5,6-tetrahydro1,3/oxazine Step A dl N-[α-phenyl(trifluoroethyl)] N'-(δ-chloropropyl)Urea

Using the same procedure as in example III at step A and starting fromdl α-phenyl (trifluoroethyl) amine and δ-chloropropyl isocyanate dlN-[α-phenyl (trifluoroethyl)] N'-(δ-chloropropyl) Urea is obtained witha quantitative yield and is used as such for the next step.

Step B dl 2-(α-trifluoromethyl benzylamino) 4,5,6-tetrahydro 1,3-oxazine

Using the same procedure as in example III at step B, dl2-(α-trifluoromethyl benzylamine) 4,5,6-tetrahydro 1,3-oxazine isobtained with a yield of 30%. This compound melts at 113°-115°(isopropyl ether)

    ______________________________________                                        Analysis C.sub.12 H.sub.13 F.sub.3 N.sub.2 O = 258,24                                     C       H         N %                                             ______________________________________                                        Calculated    55,81     5,01      10,85                                       Found         55,32     5,29      10,65                                       ______________________________________                                    

EXAMPLE VI dl 2-(αtrifluoromethyl benzylamino) thiazoline

7.1 g of dl α-phenyl (trifluoroethyl) amine are dissolved in 75 mldimethyl formamide and 26 g of 2-methylthiothiazoline are added thereto.The mixture is heated to reflux for 1 hour then let to revert at ambienttemperature. The mixture is diluted with an equal volume of isopropylether. Crystallisation of the hydroiodide is initiated by scratchingthen the crystalline suspension is kept in the refrigerator for a night.

The crystals are succione-filtered, dried, washed with a littleisopropyl ether and dried under vacuum.

The dl B 2-(trifluoromethyl benzylamino) thiazoline hydroiodide isdissolved in water converted into its base by adding sodium carbonateuntil basic. The aqueous mixture is extracted three times with isopropylether. The organic phases are united, washed with water, dried, filteredand distilled off.

dl 2-(α-trifluoromethyl benzylamino) thiazoline is thus obtained. Afterrecrystallisation from acetonitrile it melts at 165°-168°.

    ______________________________________                                        Analysis C.sub.11 H.sub.11 F.sub.3 N.sub.2 S = 260,28                                   C      H        N        S %                                        ______________________________________                                        Calculated  50.75    4.26     10.77  12.32                                    Found       50.60    4.37     10.83  12.75                                    ______________________________________                                    

EXAMPLE VII dl 2-α-trifluoromethyl (4-methoxy benzylamino) oxazoline

Melting point at 149°-155° (isopropanol).

EXAMPLE VIII dl 2-[α-pentafluoroethyl benzylamino] oxazoline

Using the procedure of example IV and starting from pentafluoropropiophenone the following compounds have been obtained.

(a) pentafluoropropiophenone Ketoxime MP 53° then 70° (yield 75%)

(b) dl α-phenyl(pentafluoropropyl) amine

BP=82°-90°/18 mmHg.

yield=70%.

Its hydrochloric acid addition salt melts at 178°-186°.

(c) dl N-[αphenyl (pentafluoropropyl)] N'-(β-chloroethyl) Urea

MP=78°-82°.

yield=70%.

(d) dl 2-[α-pentafluoroethyl benzylamio] oxazoline

MP=181°-183° (isopropanol).

    ______________________________________                                        Analysis C.sub.12 H.sub.11 F.sub.5 N.sub.2 O = 294.30                                     C       H         N %                                             ______________________________________                                        Calculated    48.99     3.77      9.52                                        Found         49.09     4.01      9.49                                        ______________________________________                                    

The starting material pentafluoropropiophenone is obtained according tothe process described by K. T. Duhart J of Am Chem Soc 78 (1956) 2268.

EXAMPLE IX

Using the procedure of example IV the following compounds have beenobtained

(a) (4-chlorophenyl) trifluoromethyl Ketoxime

F=68°-72°.

yield=85%.

(b) dl [α-(4-chlorophenyl) trifluoroethyl] amine

BP=104°-107°/12 mm Hg.

MP=29°-34°.

Its hydrochloride melts at 182°-189°.

(c) dl N-[α-(4-chlorophenyl) trifluoroethyl] N'-(β-chloroethyl) Urea

MP=142°-145°.

yield=75%.

(d) dl 2-[α-trifluoromethyl (4-chlorobenzyl) amino] oxazoline

MP=158°-163°.

    ______________________________________                                        Analysis C.sub.11 H.sub.10 ClF.sub. 3 N.sub.2 O =  278,66                               C      H        N        C1 %                                       ______________________________________                                        Calculated  47.41    3.62     10.05  12.72                                    Found       47.26    3.61     9.87   12.61                                    ______________________________________                                    

EXAMPLE X dl 2-[α-trifluoromethyl (furyl-2) methylamino] oxazoline

Using the same procedure as in example IV and starting from (furyl-2)trifluoromethyl Ketone obtained according to S. Clementi Ric. Sei. 37(1967) 418, the following compounds have been obtained.

(a) (furyl-2) trifluoromethyl Ketoxime

MP=103°-106°

(b) dl α-(furyl-2) trifluoroethyl amine

BP=64°-68°/20 mm Hg.

n_(D) ²⁰ =1,4175.

Its hydrochloride melts at 139°-145°.

(c) dl N-[α-furyl-2) trifluoroethyl] N'-(β-chloroethyl) Urea

MP=107°-113°.

yield 80%.

(d) dl 2-[αtrifluoromethyl (furyl-2) methylamino] oxazoline.

MP=112°-119° (sublim.) from isopropyl ether.

    ______________________________________                                        C.sub.9 H.sub.9 F.sub.3 N.sub.2 O.sub.4 = 234,17                                         C         H            N %                                         ______________________________________                                        Calculated   46,15       3,87         11,96                                   Found        46,10       3,94         11,81                                   ______________________________________                                    

This compound is soluble in the stoechiometric amount of dilutehydrochloric acid giving rise to the hydrochloride.

EXAMPLE XI dl 2-[αtrifluoromethyl (thienyl-2) methylamino] oxazolineStep A (thienyl-2) trifluoromethyl O-methyl Ketoxime

Using the same procedure as in step A of example IV and starting fromα-thienyl trifluoromethyl Ketone (described by S-Clementi Ric. Sci. 37(1967) 418).

(thienyl-2) trifluoromethyl O-methyl Ketoxime is obtained as a liquidboiling at 78°-82°/20 mm Hg.

n_(D) ²⁴ =1,4920.

Step B

dl α-(thienyl-2) trifluoroethyl amine/the O-methyl Ketoxine of step A isreduced by means of diborane in ether, giving rise to the correspondingamine with a yield of 85%.

dl α-(thienyl-2) trifluoroethylamine is a liquid boiling at 79°-81°/20mm Hg.

n_(D) ²⁰ =1,6320.

Its hydrochloride melts at 160°-162° (sublim.)

Step C dl N-[α-(thienyl-2) trifluoroethyl] N'-(β-chloroethyl) Urea

Using the same procedure as in example III step A the β-chloroethyl Ureais obtained with a yield of 70%. This compound is used as such for thenext step of the synthesis.

Step D dl 2-[α-trifluoromethyl (thienyl-2)methylamino]oxazoline

Using the same procedure as in example III step B the oxazoline isobtained with a yield of 65%.

dl 2-[α-trifluoromethyl (thienyl-2) methylamino]oxazoline afterrecrystallisation from ether melts at 138°-145°.

    ______________________________________                                        Analysis C.sub.9 H.sub.9 F.sub.3 N.sub.2 OS = 250.24                                   C       H         N         S %                                      ______________________________________                                        Calculated 43.20     3.63      11.20   12.82                                  Found      43.12     3.77      11.17   13.02                                  ______________________________________                                    

EXAMPLE XII levorotatory 2-[α-trifluoromethyl benzyl amino] oxazolineStep A

A vorotatory α-phenyl trifluoroethylamine 45 g d-tartaric acid aredissolved in 185 ml water. To this solution 52.5 g of dl α-phenyltrifluoroethyl amine are added portionwise for 6 hours while keeping astrong stirring. The mixture is thereafter kept aside for 12 hours. Theprecipitate of d-tartarate is succionfiltered and dried in an oven inthe vaccum. 51 g of d-tartarate are thus recovered melting at 115° then132°. Two further recrystallisations from water increase the meltingpoints to 118° and 134°. The optical purity of the d-tartarate isdetermined by TLC using the Mosher's Reagent as revealing agent. Thepurity is at least 96.5%.

The rotatory power of the d-tartarate is:

[α]₅₇₈ ²⁴ =-7°1 (C=5% MeOH).

[α]₃₆₅ ²⁴ =-41°5 (C=5% MeOH).

The d-tartarate is converted into the free base by adding enough sodiumhydroxide and extracting the resulting precipitate by ether. Afterevaporation of the solvent, 10.7 g of laevorotatory α-phenyltrifluoroethylamine are recovered.

BP=72-74/14 mm Hg.

yield=86%.

[α]₅₇₈ ²⁵ =<22.1° (C=1% MeOH).

[α]₃₆₅ ²⁵ ="65.5° (C=1% MeOH).

The laevorotatory isomer crystallises at a temperature lower than 30°.

Step B Laevorotatory N-[α-phenyl (trifluoroethyl)] N'-(βchloroethyl)Urea

Using the same procedure as in example III step A N-[αphenyl(trifluoroethyl)] N'-(β-chloroethyl) Urea (laevorotatory isomer) isobtained with a quantitative yield. It melts at 149°-151°.

[α]₅₈₉ ²³ =-38.1° (methanol).

[α]₂₆₅ ²³ =-141° (methanol).

Step C laevoratory 2-[αtrifluoromethyl) benzylamino] oxazoline

Using the same procedure as in example III step B 2-[α-(trifluoromethyl)benzylamino] oxazoline (laevorotatory isomer) is obtained. It melts at125°-133° (sublim.) after recrystallisation from isopropanol.

[α]₅₈₉ ²² =-87.4° (C=1% ethanol).

[α]₃₆₅ ²² =-335° (C=1% ethanol).

    ______________________________________                                        Analysis C.sub.11 H.sub.11 F.sub.3 N.sub.2 O = 244,22                                    C         H            N %                                         ______________________________________                                        Calculated   54.10       4.54         11.47                                   Found        54.36       4.87         11.39                                   ______________________________________                                    

Laevorotatory 2-[α(trifluoromethyl) benzylamino] oxazoline is soluble indilute hydrochloric acid. By evaporing the solvent off, thehydrochloride is recovered.

EXAMPLE XIII dextrorotatory 2-[(α-trifluoromethyl) benzylamino]oxazoline

From the mother liquors of the d-tartarate, the d-tartarate of thedextrorotatory isomer is recovered by concentration. It is furtherconverted into the free base.

BP=74°-75°/15 mm Hg.

[α]₅₈₉ ²⁵ =+23.5° (C=1% methanol).

[α]₃₆₅ ²³ =+69.8° (C=1% methanol).

dextroratatory α-phenyl trifluoroethylamine is then converted intoN-[αphenyl(trifluoroethyl)] N'-(βchloroethyl) Urea (dextrorotatoryisomer) which melts at 148°-151° (yield 83.5%).

[α]₅₈₉ ²³ =+38.2° (methanol).

[α]₃₆₅ ²³ =+141.7° (methanol).

The β-chloroethyl urea is cyclised into the oxazoline by heating in thepresence of aqueous triethylamine. Dextrorotatory 2-[(α-trifluoromethyl)benzylamino] oxazoline melts at 127°-132° (from isopropanol)

[α]₅₈₉ ²² =+87°6 (C=1% ethanol).

[α]₃₆₅ ²² =+335.8° (C=1% ethanol).

    ______________________________________                                        Analysis C.sub.11 H.sub.11 F.sub.3 N.sub.2 O = 244,22                                    C         H            N %                                         ______________________________________                                        Calculated   54.10       4.54         11.47                                   Found        53.94       4.84         11.45                                   ______________________________________                                    

EXAMPLE XIV dl α-trifluoromethyl 2-[(N-methylpyrrolyl-2) methyl amino]oxazoline Step A (N-methyl pyrrolyl-2) trifluoromethyl Ketone

In a boiler under pressure 81 g N-methyl pyrrole 241 g trifluoro aceticanhydride and 350 ml dichloroethane are introduced. The mixture is keptat about 100° for 12 hours therein. The inner temperature is let torevert to ambient temperature and the solvent is evaporated off. Thedark residue is taken up in ether, the insoluble matters are segeratedby filtration and the clear filtrate is evaporated off. The oily residueweighing 198 g is purified by fractional distillation under reducedpression -12 g of a fraction boiling at 69°-71°/15 mm Hg is recovered.The yield amounts of 72%.

(N-methylpyrrolyl-2) trifluoromethyl Ketone is a liquid.

n_(D) ²⁴ =1,4572.

Infra Red Spectrum: compatible with the proposed structure.

Stretchings at 1670 cm⁻¹ (carbonyl band).

Stretchings attributed to the CF₃ group.

NMR spectrum: in accordance with the proposed structure.

2 protons of the ring at 7.3 ppm.

1 proton of the ring at 6.4 ppm.

3 protons of the methyl group singulet at 4,0 ppm.

This compound gives rise to only one peak in VPC.

Step B

(N-methyl pyrropyl-2) trifluoromethyl Ketoxime Using the same procedureas in example IV step A and starting from (N-methyl pyrrolyl-2)trifluoromethyl Ketone, the corresponding Ketoxime is obtained with ayield of 45%.

MP=69°-71° (sublim).

    ______________________________________                                        Analysis C.sub.7 H.sub.7 F.sub.3 N.sub.2 O = 192.15                                      C         H            N %                                         ______________________________________                                        Calculated   43.76       3.76         14.58                                   Found        43.72       3.76         14.36                                   ______________________________________                                    

Step C dl [(N-methylpyrrolyl-2) methyl]α-trifluoromethyl amine

Using the same procedure as in example IV step B and starting from 11 gof the Ketoxime of step B, dl [(N-methylpyrrolyl-2) methyl]α-trifluoromethyl amine is obtained. It boils at 84°-90°/18 mm Hg. Itshydrochloride melts at 150° then 168° (dec).

    ______________________________________                                        Analysis C.sub.7 H.sub.9 N.sub.2 F.sub.3 C1H = 214,65                                  C       H         N         C1 %                                     ______________________________________                                        Calculated 39.34     4.72      13.11   16.60                                  Found      39.33     4.82      13.01   16.45                                  ______________________________________                                    

Step D dl N-[2-N(methylpyrrolyl-2) trifluoroethyl] N'-(β-chloroethyl)Urea

Using the same procedure as in example III step A and starting from 3.45g of dl [(N-methyl pyrrolyl-2) methyl] α-trifluoro methyl amine,hydrochloride, 2.7 g of the β-chloroethyl Urea are obtained in twocrops, melting at 131°-136°.

Infra Red spectrum: in accordance with the structure.

Stretchings at 3300 and 3360 cm⁻¹ (band NH).

Stretchings at 1640 and 1570 cm⁻¹ (band carbonyl).

Step E dl-αtrifluoromethyl 2-[(N-methylpyrrolyl-2) methylamino]oxazoline

Using the same procedure as in example III step B, the oxazoline isobtained with a yield of 37%. It melts at 156°-167° (sublim).

This compound is soluble in a N/10 aqueous solution of hydrochloricacid.

    ______________________________________                                        Analysis C.sub.10 H.sub.12 F.sub.3 ON.sub.3 = 244,01                                     C         H            N %                                         ______________________________________                                        Calculated   48.58       4.89         16.99                                   Found        48.51       4.94         16.78                                   ______________________________________                                    

Infra Red spectrum: in accordance with the proposed structure.

Stretchings at 3300 and 2500 cm⁻¹ (--NH).

Stretchings at 1700 cm⁻¹ (--C═N).

EXAMPLE XV dl α-trifluoromethyl 2-(N-methylbenzylamino) oxazoline Step Adl N-methoxycarbonyl α-trifluoromethyl benzylamine

In three-neck flask they are successively introduced 35 g α-phenyltrifluoroethylamine, 20.2 g triethyl amine, 200 ml tetrahydrofuran thena solution of 19 g methyl chloroformate in 40 ml tetrahydrofuran whilecooling at about 5°-10°. The temperature of the mixture is kept at about5° for 1 hour then let to revert to about 20°. The appeared precipitateis separated by filtration and the filtrate is evaporated by dryness-45.3 g of a raw product are obtained which are purified byrecrystallisation from isopropanol.

dl N-methoxycarbonyl α-trifluoromethyl benzylamine melts at 90°-94°.

Infra spectrum: in accordance with the structure.

stretchings at 3300 cm⁻¹.

stretchings at 1680 cm⁻¹ (carbonyl band).

Step B

dl N-methyl α-trifluoromethyl benzylamine. In a flask 9.5 g lithiumaluminium hydride and 100 ml tetrahydrofuran are added, then slowly asolution of 23.3 g of dl N-methoxycarbonyl α-trifluoromethyl benzylaminein 100 ml tetrahydrofuran is poured thereto. The whole mixture is heatedto reflux for 6 hours. After cooling, the excess of reagent is destroyedby cautious addition of a dilute solution of sodium hydroxide, then ofwater. The appeared precipitate is separated by filtration, washed withfew ml of tetrahydrofuran and the washings are added to the filtrate.The organic solutions are evaporated to dryness and the dry residueweighing about 14 g is taken up in methylene chloride. After renewedextractions with 20% hydrochloric acid and basification of the acidsolutions by addition of sodium hydroxide, an oily residue is recovered.It is further dissolved in ether, the ethereous solution is washed withwater, dried on sodium sulphate, filtered and evaporated off -8.4 g dlN-methyl α-trifluoromethyl benzylamine are recovered in the form of acolourless liquid boiling at 68°-70°/12 mm Hg

n_(D) ²² =1,4560.

    ______________________________________                                        Analysis C.sub.9 H.sub.10 NF.sub.3 = 189,2                                               C         H            N %                                         ______________________________________                                        Calculated   57.13       5.33         7.40                                    Found        57.02       5.37         7.02                                    ______________________________________                                    

Infra-Red spectrum: lack of carbonyl band.

Step C dl N-[N-methyl(α-phenyl)trifluoroethyl]N'-(β-chloroethyl Urea

Using the same procedure as in example IV step A, 9.2 g of thecorresponding β-chloroethyl Urea are obtained, melting at 70°-80°.

    ______________________________________                                        Analysis C.sub.12 H.sub.14 N.sub.2 ClF.sub. 3 = 275,47                                 C       H         N         Cl %                                     ______________________________________                                        Calculated 48.90     4.79      9.51    12.04                                  Found      48.36     4.92      9.65    11.98                                  ______________________________________                                    

Step D dl N-methyl 2-(α-trifluoromethylbenzylamino)oxazoline

8.4 g of dl N-[N-methyl(α-phenyl)trifluoroethyl]N'-(β-chloroethyl)Ureaare suspended in 77 ml water 7 ml triethylamine are added thereto andthe mixture is heated to reflux for 21/2 hours. After cooling in anice-bath, an oily product precipitates. It is extracted four times withmethylene chloride. The methylenic solutions are united and extractedwith hydrochloric acid. The aqueous phase is separated, then made basicby adding enough ammonia. The so-formed suspension is let in a coolplace for a night. The insoluble matters are separated and taken up inmethylenechloride. The methylenic phase is purified as usual andevaporated off -6.1 g of an oily product are recovered which is purifiedby dissolving it in the minimal amount of ether and filtering theorganic solution.

After evaporation of the solvent 4.7 g of pure dl N-methyl2-(α-trifluoromethyl benzylamino)oxazoline are obtained as a viscousliquid soluble in the most of the organic solvents and in an aqueoussolution ofhydrochloric acid.

Infra Red spectrum: in accordance with the structure.

stretchings at 1650 cm⁻¹ (group C═N).

lack of Carbonyl band.

EXAMPLE XVI dl α-trifluoromethyl 2-[(pyrrolyl-2)methylamino]oxazoline

Using the same procedure as in example XIV and starting from(pyrrolyl-2) trifluoromethyl Ketone, they are obtained:

O-methyl(pyrrolyl-2)trifluoromethyl Ketoxime

dl α-trifluoromethyl(pyrrolyl-2)methylamine

dl N-[α-trifluoromethyl(pyrrolyl-2)methyl]N'-(β-chloro ethyl)Urea.

dl α-trifluoromethyl 2-[(pyrrolyl-2)methyl amino]oxazoline.

MP=125°-132° (from ether).

This compound is soluble in the stoichiometric amount of N/10 aqueoussolutions of hydrochloric acid.

    ______________________________________                                        Analysis C.sub.9 H.sub.10 F.sub.3 N.sub.3 O = 233,19                                     C          H           N %                                         ______________________________________                                        Calculated   46.35       4.33         18.03                                   Found        46.33       4.46         17.82                                   ______________________________________                                    

NMR Spectrum: in accordance with the structure

    ______________________________________                                        5      aromatic protons at 7.4 ppm                                             1                                                                                    ##STR30##                                                             2      methylenic protons CH.sub.2 O at 4.3 ppm                               2      methylenic protons CH.sub.2 N = at 3.8 ppm                                     ##STR31##                                                             ______________________________________                                    

EXAMPLE XVII

Tablets containing 1 mg dl 2-[(α-trifluoromethyl benzylamino)]oxazoline

    ______________________________________                                        dl 2-[(α-trifluoromethyl benzylamino)] oxazoline                                                    10     g                                          Mais starch                 250    g                                          Wheat starch                50     g                                          Carboxymethyl starch        20     g                                          Calcium carbonate           120    g                                          Calcium phosphate           140    g                                          Ethyl cellulose             4      g                                          Talc                        4      g                                          Magnesium stearate          2      g                                          ______________________________________                                    

For 10.000 tablets weighing about 0.060 g each.

EXAMPLE XVIII Pharmacological study of the compounds according to theinvention

(a) determination of the acute toxicity

The average lethal dosage (LD₅₀) is determined on batches of mice (swissstrain) weighing about 20 g, by intraperitonal injections of increasingdoses of the compounds to be tested.

The animals are kept under survey for 8 days and the deaths, if any, arenumbered. The lethal dosage is graphically determined according to themethod of Tainter and Miller.

The compounds of general formula I have been injected at doses rangingfrom 20 to 200 mg/Kg. In general the lethal dosage is about 200 mg/Kg.The only manifestations of toxicity in the animals are sedation andpiloerection.

(b) determination of the hypotensive activity

The compounds of general formula I have been tested for hypotensiveactivity in lots of dogs, previously anesthetized with intravenousabutal which received the compound to be tested at doses ranging from 2to 0.5 mg/Kg by intravenous way. At the lowest doses the decrease of thein arterial pressure is only short-lasting but the cardiac rhythm issignificantly decreased for a period of about 30 mm.

Higher doses induce at first a slight increase of the arterial pressurethen a significant decrease. The cardiac rhythm is largely depressed andthis decrease may be as high as 50% of the normal cardiac rhythmobserved in the controls.

(c) search of a neurological effect

in the mice (strain CD) doses of 10 and 20 mg/Kg through intravritoneousway induce only a decrease of the motility, a decrease of a bodytemperature, a decrease in the food and drink intake.

In the rats (strain LE), small doses induce a state of excitation, andpilo-erection. Higher doses induce a decrease of the motility and of themuscular tone.

In the cats the administration of the compounds induce at first citationthen a weak depressive state.

Therefore the compounds of general formula I appear to be imulant agentof the central noradrenergic receptors and they cause inhibition of thesympathic tone, hypotension and brady cardia. They are activeparenterally as well as per oral way.

EXAMPLE XIX Preparation of dl 2-[(2-methylphenyl)α-trifluoroethyl]aminozoline and its fumaric acid addition salt Step A

3-methyl trifluoroacetophenone In a three-neck flask fitted withmechanical stirring device and a pipe for an inert gas 41 g. of o,bromotoluene 300 ml ether are mixed together until a clear solution isobtained 5.85 g magnesium turnings then few crystalls of iodine arecautiously added. The mixture is heated to reflux under stirring. Whenall the magnesium has reacted the mixture is let to revert to roomtemperature and a solution of 6,16 ml trifluoroacetic acid in 15 mlether is slowly added in about 10 mn. After completion of the additionthe mixture is heated to reflux for 1.30 h and kept thereafter aside for36 hours. The reaction mixture is poured on a mixture of 150 g crushedice and 24 ml 30% hydrochloric acid. The ethereous phase is separatedand the aqueous phase is extracted twice with 25 ml ether. The organicphases are united, washed with water, with an aqueous solution of sodiumbicarbonate and further with water until the washings are neutral.

The solution is dried an sodium sulphate, filtered and distilled off.The dry residue is further purified by fractional distillation underreduced pressure. The fraction distilling at 60°-100° under 35 mm Hg isrecovered. A renewed distillation allows the obtention of the mainfraction boiling at 80°-85° under 35 mm Hg. This fraction weighs 9.1 gi.e. a yield of 60%.

INFRA-RED SPECTRUM:

Stretching at 1710 cm⁻¹ (carbonyl function).

Weak absorption at 3600-3800 cm⁻¹ in occordance with the structure.

Step B (2-methylphenyl)trifluoromethyl ketoxime

Using the same procedure as in example IV step A and starting from 7.5 gof 2-methyl trifluoroacetophenone, there was obtained 4.75 g of thecorresponding oxime. It melts at 63.65°.

Step C dl[(2-methylphenyl)αααtrifluoroethyl]amine

Using the same procedure as in example IV step B and starting from 4 g(2-methylphenyl)trifluoromethyl ketoxime, 2.8 g[(2-methylphenyl)ααα-trifluoroethyl]amine are obtained as an oil.

Step D dl N-[(ααα-trifluoromethyl) (2methylphenyl)N'-(α-chloroethyl)]Urea

Using the procedure of example III Step A and starting fromdl[(2-methylphenyl)ααα-trifluoroethyl]amine, dlN-[(2-methylphenyl)ααα-trifluoromethyl]N'-(β-chloroethyl)Urea isobtained with a yield of 78%. It is used as such for the next step ofthe synthesis.

Step E dl 2-[(2-methylphenyl)αααtrifluoroethyl]amino oxazoline

Using the same procedure as in example XV Step D and starting from thetotal amount of dl N-[(2 methylphenyl)ααα-trifluoromethyl]N'-(βchloroethyl)Urea obtained at Step D, 1.41 g of dl2-[(2-methylphenyl)ααα-trifluoroethyl]amino oxazoline are produced as aliquid soluble in the usual organic solvents and in the aqueous solutionof mineral acids.

Step F Production of the fumaric acid salt

0.53 g of the oxazoline of step D is dissolved in 5 ml ether. To thissolution a solution of 0.25 g fumaric acid in 4 ml ether is dropwiseadded. Crystallisation is initiated by scratching and the mixture iskept aside for a night in a cool place.

The crystalls are succion-filtered, washed with the minimal amount ofether and dried in vaccuo. Thus 0.42 g of the acid fumarate is obtainedas white crystalls which melts at 135°-137°. For analytical purposes theacid fumarate is recrystallized from acetonitrile. The melting pointremains unaltered.

What we claim is:
 1. The oxazoline(trifluoroethyl)amines of the formula ##STR32## wherein R₁ and R₂, the same or different, are hydrogen, a lower alkoxy radical of 1 to 6 carbon atoms, inclusive, a lower alkylradical of 1 to 6 carbon atoms, inclusive, or a halogen,R₃ is hydrogen, a methyl or an ethyl radical, R₄ is hydrogen, a methyl, an ethyl or a cyclopropyl radical, R is a hydrogen when R₁ and/or R₂ are different from hydrogen, or is a lower alkyl of 1 to 6 carbon atoms, inclusive, when R₁ and/or R₂ are hydrogen, R₅ is hydrogen or a lower alkyl radical of 1 to 6 carbon atoms, inclusive, and n is zero, 1 or
 2. 2. The salts of a compound of formula I with mineral or organic acid, preferably a therapeutically-compatible mineral or organic.
 3. The optically-active isomers of a compound of formula I or an acid addition salt thereof.
 4. An of formula I_(A), in racemic or form ##STR33## wherein the substituents R, R₁, R₂, R₃, R₄ and n are defined according to claim
 1. 5. dlα-trifluoromethyl 2-(N-methylpyrrolyl-2)methylamino oxazoline according to claim
 1. 6. dl α-trifluoromethyl 2-[(pyrrolyl-2)methyl amino]oxazoline according to claim
 1. 